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Journal of Feline Medicine and Surgery (2015) 17, 220234

CLINICAL REVIEW

UPDATE IN FELINE THERAPEUTICS

Clinical use of 10 emerging
therapies
William Whitehouse and Katrina Viviano
Practical relevance: The field of
veterinary medicine is constantly
evolving. New medications are being
introduced into clinical practice, and
novel uses for established medications
are frequently being discovered as new
information comes to light.
Clinical challenges: Therapeutic options for
our feline patients can be restricted based on
inadequate clinical evidence, adverse effects and
patient compliance concerns. Additionally, with the
reduced availability of commonly used medications
in some regions, clinicians are forced to utilize
alternatives with which they may have limited
experience.
Audience: This review article is directed towards
primary care veterinarians working with feline
patients. The selection of medications discussed
is based on many of the clinical challenges
commonly encountered in practice.
Evidence base: The evidence for use of some
of these medications is limited due to their novelty.
Known mechanisms of action, pharmacokinetic
and pharmacodynamics data, adverse effects
and clinical uses are reviewed where possible,
with clinical recommendations made based on
the evidence of data available.

Robenacoxib
Pharmaceuticals
discussed in this
review

Non-steroidal
anti-inflammatory
drugs
(NSAIDs) are frequently used medications in
veterinary medicine, especially for the treatment of pain and inflammation associated with
musculoskeletal disorders. Mechanistically,
NSAID effects are achieved through the
inhibition of cyclooxygenase (COX), the enzyme
needed in the conversion of arachidonic acid to
prostaglandins and thromboxane A2 (see box
below). COX-1 is constitutively expressed in
most tissues in the body and is responsible for
the mediation of many physiological reactions
including gastrointestinal (GI) mucosal defense. As such, many of the toxicities associated

<
<
<
<
<

<
<
<
<
<

Robenacoxib
Pradofloxacin
Cefovecin
Minocycline
Ciclosporin
(cyclosporine)
Pimobendan
Clopidogrel
Mirtazapine
Famciclovir
Oclacitinib

COX targets of NSAIDs and the associated

physiological response of COX-1 vs COX-2 isoforms
Physiological stimulus

Inflammatory stimulus
Inhibition by
NSAID
COX-2 INDUCIBLE
Site of inflammation

COX-1 CONSTITUTIVE
Kidneys, GI tract,
platelets, endothelium

Inflammatory
prostaglandins, free
radicals, proteases

Prostaglandins,
prostacyclins,
thromboxanes

Physiological functions

Inflammation

William Whitehouse
DVM
Katrina Viviano
DVM PhD DACVIM DACVCP
Department of Medical Sciences, School of
Veterinary Medicine, University of Wisconsin,
2015 Linden Drive, Madison, WI 53706, USA
*Corresponding author:
viviano@svm.vetmed.wisc.edu

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DOI: 10.1177/1098612X15571879
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with NSAIDs (primarily GI) are thought to be

due to inhibition of COX-1. COX-2 is
expressed by cells involved in inflammation
and is an inducible isoform that is
largely responsible for the production of
inflammatory prostaglandins; however, it is also
expressed in other tissues, such as the kidney,
rendering the kidney susceptible to toxicity as
well.
Selective COX-2 inhibitors (the coxibs) were
developed to block inducible cyclooxygenase,
thus in theory leaving COX-1 and mucosal
defenses intact. Subsequent investigation into
the COX isomers has shown that the molecules are actually very similar, leading to the
idea that it may be difficult to attain true selectivity.1 Robenacoxib (Onsior; Novartis Animal
Health) is a new highly selective COX-2
NSAID2,3 available for use in cats >2.5 kg and
>6 months of age. In the United States,
robenacoxib is approved by the Food and
Drug Administration (FDA) for the treatment
of postoperative pain and inflammation at a
dosage of 12 mg/kg/day for a maximum of
3 days. In Europe, the 6 mg flavored tablets
are approved for the treatment of acute pain
and inflammation associated with musculoskeletal disorders in cats for 6 days. The
20 mg/ml solution for injection may be given
at a dose of 2 mg/kg subcutaneously for up to
2 consecutive days for pain associated with
both orthopedic and soft tissue surgery in
Europe. Currently, there is no approval for
injection followed by oral administration of
robenacoxib.
When administered orally on an empty
stomach, the bioavailability of robenacoxib is
approximately 50%, and it decreases significantly when given after a meal.4 The drug
appears to be absorbed rapidly and reaches
peak plasma concentrations in 30 mins in fast-

Robenacoxib
is a selective
COX-2 inhibitor
approved for
use in cats
up to 3 days
in the USA and
up to 6 days
in Europe.

Figure 1 Due to the

increased risk of acute
kidney injury, robenacoxib,
as well as other NSAIDs,
should only be given to
patients undergoing
orthopedic (or soft tissue)
surgery after recovery
from general anesthesia.
Courtesy of Sarah Dowling

ed patients. Food causes high variability in

the time to reach maximum concentration (up
to 8 h).4 Consequently, robenacoxib should
be given to cats on an empty stomach or with
only a small amount of food. Although the
drug has a short elimination half-life of
approximately 4560 mins, depending on
route of administration, mean residence time
in exudate at sites of inflammation is close to
24 h regardless of administration type.5 This
extended pharmacodynamic effect of robenacoxib allows for once daily dosing in cats.
Robenacoxib has been used effectively in
cats for the treatment of acute pain and
inflammation associated with musculoskeletal disorders,6,7 ovariohysterectomy8 and
other surgical procedures.9 It is important to
note that robenacoxib has not been evaluated
for the treatment of chronic pain and inflammation; therefore, its current recommended
use is limited to acute pain management.
Robenacoxib appears to be well tolerated in
these clinical trials as well. A safety study
showed that oral robenacoxib is well tolerated
in cats at doses as high as 10 mg/kg q12h for
42 days.10 However, the population of this
study was comprised of young, healthy cats
all less than 1 year of age, making it extremely
difficult to extrapolate this safety information
to an older population.
NSAIDs should be used judiciously in cats
with comorbidities such as renal, GI, hepatic
or cardiac disease.11 Evaluation of serum renal
and liver parameters is recommended prior to
use of robenacoxib. In cases of known renal
or hepatic disease, dose reduction or alternative therapy (which may be achieved by
adjunctive analgesia), as well as monitoring
following treatment, is recommended.
With specific regard to renal disease, COX-2
is constitutively expressed in the mammalian
kidney and is responsible for maintaining
renal blood flow in response to states of actual
or perceived decreases in intravascular
volume.12 NSAIDs will inhibit formation
of prostaglandins and their compensatory
effects in the kidneys in response to hypovolemia, which will lead to renal ischemia and
acute kidney injury. As such, NSAIDs including robenacoxib should not be used in
patients that are dehydrated or prior to anesthetic events where hypotension is a risk factor (Figure 1). Opioids should be considered
for preoperative or perioperative analgesia.11
It is our recommendation that NSAIDs be
used in the postoperative period when the
risk of hypotension is minimized. Additionally, owners should be specifically
instructed to discontinue robenacoxib if the
patient develops any clinical signs of systemic
illness including anorexia, vomiting and
diarrhea.

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Antibiotic stewardship
As antimicrobial resistance becomes an increasing
concern in both veterinary and human medicine, the
inappropriate and overuse of antibiotics must be
avoided. Recent veterinary reports on the use of
antibiotics in primary care facilities13,14 as well as
teaching hospitals15,16 document the need for
improved global antibiotic stewardship. The American
Veterinary Medical Association and Canadian
Veterinary Medical Association have recognized the
great need for implementing antimicrobial stewardship programs. The American College of Veterinary
Internal Medicine has produced a consensus statement regarding antimicrobial use in veterinary medicine;17 however, no official antimicrobial stewardship
program currently exists in the United States.
Fortunately, these programs have already been instituted in some countries such as PROTECT by the
British Small Animal Veterinary Association.
Overall, our profession significantly lags behind
our human counterparts in developing and enforcing
antimicrobial stewardship programs, especially with
regard to companion animal medicine.

Responsible antibiotics use

Pharmaceutical companies are required
to provide data sheets for all prescription
medications. They contain detailed information on these medications, including
indications for use. Antibiotics, including
those that are discussed within this
review, are commonly indicated for treatment of bacterial infections including
urinary tract infections, respiratory infections and pyodermas. Although a particular antibiotic may have a reported
use, the clinician must exercise good
judgment when prescribing medications.
Antibiotic selection should ideally be
based on culture and susceptibility
results, using narrow-spectrum antibiotics given for the shortest duration
possible when available.

Pradofloxacin
Fluoroquinolones are commonly used antibiotics in veterinary medicine. FDA-approved
fluoroquinolones include enrofloxacin, orbifloxacin, difloxacin (dogs only), marbofloxacin
and, recently, pradofloxacin. They are classified into generations based on differences in
chemical structure that influence their spectrum of activity.18 Enrofloxacin, difloxacin,
marbofloxacin and ciprofloxacin are secondgeneration fluoroquinolones. Third-generation fluoroquinolones have an increased
gram-positive and anaerobic spectrum, with
orbifloxacin and pradofloxacin falling into this
category. Pradofloxacin (Veraflox; Bayer
HealthCare) is now licensed in Europe for a
broad range of bacterial infections in dogs and
cats, but is only licensed for cats in the USA.
The antibacterial action of fluoroquinolones is
achieved through inhibition of topoisomerase
activity. Pradofloxacin inhibits both topoisomerase I (DNA gyrase) and topoisomerase IV,
resulting in a broader spectrum of activity compared with earlier generation fluoroquinolones.
Pradofloxacin maintains excellent gram-negative coverage and has shown efficacy against

Pradofloxacin is an antibiotic with coverage

against gram-positive, gram-negative and
anaerobic organisms.

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As a profession
we lag
significantly
behind our
human
counterparts
in developing
and enforcing
antimicrobial
stewardship
programs.

Mycoplasma,19,20 Bartonella21 and some intracellular bacteria such as Mycobacterium.22 In

addition, pradofloxacin has shown good antianaerobe activity in vitro;23 however, its clinical
efficacy in the treatment of anaerobic infections
in vivo remains to be determined.
Reported indications for pradofloxacin in
cats include infected wounds and abscesses,
bacterial urinary tract infections, bacterial
upper respiratory tract infections and hemotropic mycoplasmosis.19,24,25
In cats with upper respiratory infections
due to Chlamydia felis or Mycoplasma species,
pradofloxacin showed similar efficacy in
terms of resolution of clinical signs as doxycycline; however, in some cats treated with
pradofloxacin C felis DNA persisted.20
Pradofloxacin has also shown equivalent efficacy (ie, clinical disease recovery) as doxycycline therapy in the treatment of experimental Mycoplasma hemofelis infection. In cats
experimentally infected with M hemofelis,
6/12 cats treated with pradofloxacin (four
administered 5 mg/kg/day, two administered 10 mg/kg/day) tested M hemofelis negative with quantitative PCR of blood at the end
of the study, while none of the cats treated
with doxycycline tested PCR negative,19 suggesting that pradofloxacin may be effective in
the treatment of M hemofelis infection in cats.
However, negative PCR results alone should
not be interpreted as a reliable marker of
clearance of infection due to the potential for
organism sequestration.

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Rational indications for the clinical use of

pradofloxacin include infections where gramnegative enteric organisms and anaerobes are
expected, such as hepatobiliary infections,
aspiration pneumonia and septic peritonitis,
with empirical use reserved for serious
life-threatening infections that are likely to
be resistant to first-generation antibiotics.
Pradofloxacin may also be a good choice
for the treatment of pyothorax where
Pasteurella and mixed anaerobes are expected.
Pradofloxacin is unlikely to be clinically
effective in the treatment of Nocardia infection
despite lower mean inhibitory concentration
(MIC50 and MIC90) values for Nocardia isolates compared with enrofloxacin and
ciprofloxacin.22 As with any antibiotic use,
there is the concern of selecting for bacterial
resistance with overuse or inappropriate use
(see box on page 222); therefore, culture and
susceptibility testing is recommended when
possible to support the need for treatment
with a third-generation fluoroquinolone.
Pradofloxacin is reported to be well tolerated in cats.19,24 A unique concern with this class
of antibiotics in feline patients is acute diffuse
retinal degeneration. This species-specific
adverse reaction is dose-dependent and
results from a deficiency in the ATP-binding
cassette subfamily G member 2 protein
(ABCG2). This proteins role is to prevent
xenobiotics, which include the photosensitive
fluoroquinolones, from crossing the blood
retinal barrier into the retina.26 Cats treated
with high doses or given a moderate overdose
of a fluoroquinolone, given rapid intravenous
infusions, treated with a prolonged antibiotic
course, or those with decreased clearance due
to a decreased glomerular filtration rate are at
increased risk of acute retinal degeneration
and blindness.27 This adverse reaction has not
been reported with pradofloxacin or marbofloxacin. Pradofloxacin appears to have low
retinotoxic potential, with no retinal changes
noted at 50 mg/kg/day.28 However, all fluoroquinolones should be considered to have
the potential to cause retinal toxicity in cats
(Table 1).

Table 1

Cefovecin

Cefovecin
is not an
appropriate
antimicrobial
choice where
only short-term
therapy is
required; for
example,
perioperative
surgical
prophylaxis.

Summary of post-approval studies that have evaluated

the dosage of veterinary-approved fluoroquinolones
associated with retinal degeneration in young healthy cats

LD
Fluoroquinolone (mg/kg/day)

No RL
Multiple
(mg/kg/day) of LD

RD
(mg/kg/day)

Multiple
of LD

Enrofloxacin27,29

x1

20

x4

Orbifloxacin27

2.5

15

x6

45

x 18

Marbofloxacin27

2.75

55

x 20

N/A

N/A

Pradofloxacin28

7.5

50

x6

N/A

N/A

LD = label dose; No RL = no retinal lesions; RD = retinal degeneration

Cefovecin (Convenia; Pfizer Animal Health)

is a semi-synthetic third-generation cephalosporin approved for use in cats for skin and
soft tissue infections such as pyoderma,
wounds and abscesses,30,31 as well as for lower
urinary tract infections.32 It has bactericidal
activity against gram-positive, gram-negative
and anaerobic bacteria. However, its
spectrum of activity is closer to first-generation antibiotics of this class, with coverage for
Escherichia coli, Staphylococcus pseudintermedius
and Pasteurella multocida but poor activity
against Pseudomonas aeruginosa. As with other
cephalosporins, cefovecin lacks activity
against Enterococcus species.33
Cefovecin is fully bioavailable when administered subcutaneously in cats. It reaches peak
plasma concentrations in approximately 2 h
and is over 99% bound to plasma proteins.34
As a result, its half-life is extended (nearly 7
days), allowing it to maintain therapeutic concentrations against P multocida in plasma and
dermal transudate as well as against E coli in
urine for 14 days. Cefovecins extended elimination half-life enables less frequent dosing
but precludes drug withdrawal after the
development of adverse reactions as well as
early antibiotic de-escalation, which may contribute to the development of antimicrobial
resistance. Consequently, cefovecin is not an
appropriate choice for surgical infection prophylaxis where only short-term therapy is
required and the risk of colonizing postoperative patients with resistant bacterial strains
may be increased. For example, the impact of
cefovecin on fecal enteric flora was evaluated
in healthy dogs following the administration
of a single 8 mg/kg subcutaneous dose.35
In the cefovecin-treated dogs the number of
E coli isolates decreased and Enterococcus
species isolates increased. In addition, significantly more cefovecin-resistant E coli was
isolated in the cefovecin-treated dogs on days
7, 14 and 28.
Cefovecin is often an appealing antibiotic
choice in cats because of its long duration of
action and ability to ameliorate the concern
for patient and client compliance, but its use
in the treatment of common feline conditions
that can be successfully treated without
antibiotics or with narrower spectrum antibiotics needs to be questioned. For example,
reported uses of cefovecin have included the
treatment of conditions with low incidence of
bacterial infections (ie, upper respiratory tract
disease, most commonly caused by an underlying viral etiology, and lower urinary tract
disease, commonly an inflammatory disease
in this species).14 Although the development
of a secondary bacterial infection can compli-

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cate upper respiratory tract disease in some

cats, the more common bacterial species associated with feline upper respiratory disease
(eg, Mycoplasma species, Bordetella bronchiseptica and Chlamydophila felis) are not expected to
be effectively treated with cefovecin. Both
doxycycline and amoxicillinclavulanic acid
have displayed higher efficacy when compared with cefovecin for the treatment of
upper respiratory tract disease in shelter cats
in a randomized prospective clinical trial.36
In our veterinary patients this long-duration-of-action cephalosporin should be
considered a second-line antibiotic and used
clinically based on culture and susceptibility
testing. In the cephalosporin class, the third
and fourth generations are considered to be
critically important antimicrobial groups in
human medicine that should be reserved to
treat life-threatening diseases that have a
limited number of therapeutic options.

Minocycline
Minocycline is a semi-synthetic antibiotic in
the tetracycline class produced from natural
antibiotics such as tetracycline and oxytetracycline. It is a broad-spectrum bacteriostatic
antibiotic that inhibits protein synthesis by
reversibly binding to the 30S ribosomal subunit.37 It is highly lipophilic and able to cross
the bloodbrain barrier much more readily
than doxycycline in dogs.38 As a result of its
highly lipophilic nature, it is a poorer choice
for urinary tract infections compared with
other tetracyclines.
Minocycline has a similar spectrum of
activity as doxycycline. Susceptible organisms
include some gram-positive species (eg,
staphylococci and streptococci), gramnegative species (eg, Bartonella, Bordetella,
Brucella and Pasteurella), as well as other
species including spirochetes (Borrelia and
Leptospira), Chlamydia, Mycoplasma, Rickettsia
and Wolbachia. Common resistant species
include E coli, Klebsiella, Bacteroides,
Enterobacter, Proteus and Pseudomonas.
Tetracycline is routinely used as the class
indicator for in vitro susceptibility testing.
Tetracycline can reliably predict susceptibility
to doxycycline and minocycline, but some
bacterial isolates reported to be resistant to
tetracycline may still be susceptible to
doxycycline and minocycline. For example,
methicillin-resistant S pseudintermedius (MRSP)

isolates continue to be susceptible to minocycline despite developing resistance to tetracycline and doxycycline.39 To differentiate
antimicrobial susceptibility within this tetracycline class, a specialized assay is required to
identify the presence of inducible resistance
gene(s), and not all microbiology laboratories
have a validated induction susceptibility assay.
Doxycycline is a widely used antibiotic in
veterinary medicine. Due to the recent
decrease in availability and increased cost of
doxycycline in the United States, the use of
minocycline as an alternative for doxycycline
may increase in our veterinary patients in
some geographic regions. The range of
dosages recommended for cats varies anywhere from 525 mg/kg orally (PO) q12h,
with most sources recommending doses
within the lower half from 512.5 mg/kg.40
Currently, there are no published studies on
the pharmacokinetics of minocycline in cats.
However, a pharmacokinetics study in cats
that was recently presented as an abstract
recommends a dosage of 8.8 mg/kg PO q24h
(or 50 mg/cat PO q24h).41 This dosage recommendation is consistent with a recent
pharmacokinetics/pharmacodynamics study
in dogs that indicated 5 mg/kg q12h should
be an effective dosage in the treatment of
S pseudintermedius with a minimal inhibitory
concentration of <0.25 g/ml.42
The main side effect of minocycline appears
to be GI upset, which may be ameliorated by
administering the drug with or after a meal.
In dogs, the concurrent administration of
sucralfate significantly decreases the oral
bioavailability of minocycline. However, oral
bioavailability is not affected when sucralfate
is given 2 h after minocycline.43 It is recommended to avoid administration of minocycline as a rapid intravenous bolus because it
has caused urticaria and hypotension in
dogs.44 Hepatotoxicity has also been reported
secondarily to tetracycline administration in a
cat;45 therefore, clinicians should be cognisant
of increases in serum alanine aminotransferase after prescribing this medication.
In cats, the risk of focal esophageal strictures associated with oral minocycline is
unknown. This adverse effect has been reported with the hyclate (hydrochloride) salt of
doxycycline when administered orally in
cats.46,47 The mechanism responsible for this
adverse effect in cats is thought to be similar
to that in humans where the dissolution of a

Due to the unknown potential for oral minocycline to cause esophageal stricture
formation in cats, it is recommended to follow administration of the capsule with water
or food or to consider reconstituting the medication into an oral suspension.

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retained capsule or tablet coating in the

esophagus leads to a caustic burn of the
mucosa, resulting in fibrosis and a focal stricture. The risk of doxycycline-induced stricture
formation can be reduced by use of an oral
suspension or by following capsule or tablet
administration with food or water. The
administration of an oral suspension should
be considered when prescribing minocycline
(a hydrochloride salt) to a cat until more
clinical experience is gained.
Tetracyclines can chelate calcium from teeth
and bone, inhibit calcification and can cause
tooth discoloration. As a member of the tetracycline class of antimicrobials, minocycline is
excreted in the milk and has the potential to
retard fetal skeletal development and discolor
deciduous teeth. Therefore, use is best avoided in pregnant and nursing queens or young
kittens unless the benefits outweigh the risks.
Reproductive and nursing safety information
specific to minocycline is unknown. In relation to drug safety during pregnancy, the FDA
classifies tetracycline antibiotics as category
D, meaning they are contraindicated (in
pregnant humans) unless benefits outweigh
the risks. Amoxicillin, amoxicillinclavulanic
acid, ampicillin, cephalexin, clindamycin,
erythromycin and azithromycin are examples
of antibiotics that are relatively safe and
should be used in lieu of minocycline in
pregnant or nursing queens or young kittens
if possible.

Ciclosporin
Ciclosporin (cyclosporine) A (CsA) is a commonly used immunomodulatory medication in
veterinary medicine. CsA binds to intracellular
protein cyclophilin-1, forming a complex that
inhibits calcineurin. As a result, the nuclear factor of activated T cells is inhibited, leading to
decreased production of several principal
proinflammatory cytokines such as interleukin
(IL)-2, IL-4, tumor necrosis factor- and interferon-. Sandimmune (Novartis Pharmaceuticals) was found to have both poor and
highly variable oral bioavailability in human
studies,48,49 and is not routinely used in dogs or
cats. The microemulsion or modified CsA
formulation (Atopica; Novartis Animal Health)
enhances the oral absorption of this otherwise
poorly soluble drug and is approved by the
FDA for the treatment of allergic dermatitis in
cats. An oral solution (Atopica for Cats;
Novartis Animal Health), reported to be well
tolerated in cats, is available.
In cats, microemulsified CsA is rapidly
absorbed after oral administration, with
bioavailability between 25% and 29% and an
elimination half-life of approximately 8 h at a
dose of 3 mg/kg PO q12h.50 Transdermal CsA

has inconsistent absorption and does not

reach therapeutic blood concentrations in
most cats.51 In a small population of cats, ketoconazole given at 10 mg/kg PO with CsA at
4 mg/kg intravenously (IV) increased blood
concentrations of CsA approximately twofold as well as doubling the half-life from
10.722.2 h.52 Clarithromycin also appears to
increase the bioavailability of CsA, reducing
the dose needed to maintain therapeutic
trough levels by 65% and the frequency of
administration from q12h to q24h.53
CsA appears to be a well-tolerated medication.54 The most common side effects include
vomiting, diarrhea, anorexia and weight loss.
GI upset following the initiation of oral CsA
therapy in some cats is often transient or
responsive to dose reduction and may not
require drug discontinuation. Anecdotally, we
have had a positive response to giving
metoclopramide at a dose of 0.30.4 mg/kg
PO 2030 mins prior to administration of oral
CsA to cats experiencing GI upset. Rare
side effects of CsA, including gingival hyperplasia,55 as well as the development of toxoplasmosis56,57 and possible hemolytic uremic
syndrome after renal transplantation,58
require drug discontinuation. Anaphylaxis
associated with intravenous CsA has been
reported in one cat.59 CsA is also suspected to
be associated with the development of malignant neoplasia such as lymphoma in cats
receiving the medication following renal
transplantation,60 but this has not been definitively proven.61
The true incidence of opportunistic infections with CsA therapy is unknown.
Clinicians should be judicious with the use of
CsA and rule out concurrent infections as best
as possible prior to initiating therapy, using
history, physical examination and available
indicated diagnostics (eg, complete blood
count, biochemistry panel, urinalysis, feline
leukemia virus antigen and feline immunodeficiency virus antibody testing, as well as any
additional infectious disease testing as
required). Vaccine titers are adequate in CsAtreated cats receiving boosters for feline
calicivirus, feline panleukopenia virus, feline
herpesvirus-1 (FHV-1), feline leukemia virus
and rabies, but not for feline immunodeficiency virus.62

Oral bioavailability of ciclosporin is increased

and less variable with the microemulsified
(modified) version. Transdermal ciclosporin does
not reach therapeutic plasma concentrations in
most cats and is, therefore, not recommended.

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Reports of CsA use in cats have encompassed a variety of immune-mediated to allergic diseases. CsA has been used effectively in
conjunction with glucocorticoids in cats with
idiopathic pure red cell aplasia (PRCA)59 and
in a cat with primary immune-mediated
thrombocytopenia.63 The drug appears to be
effective when given topically for treatment of
proliferative feline eosinophilic keratitis.64 In a
single case report, it improved clinical signs in
a cat with chronic progressive polyarthritis.65
CsA also seems to be effective for the treatment of refractory feline stomatitis, based on
a small population of cats that had already
undergone premolarmolar or full-mouth
extractions, at a dose of 2.5 mg/kg PO q12h,
compared with placebo.66 CsA trough levels
>300 ng/ml were associated with significant
improvement in that study. Furthermore, CsA
given at doses in order to maintain trough
levels between 500 and 850 ng/ml prior to
antigen challenge in Ascaris suum-sensitized
cats (ie, cats with experimentally induced
asthma) inhibited airway hyperresponsiveness, airway inflammation and airway remodelling in the acute and chronic (6 weeks)
setting.67 Targeted trough levels for CsA are
extrapolated from human medicine, with very
few studies equating clinical status to blood
concentrations, thus making it difficult to
make generalizations and recommendations
for monitoring therapy. In one retrospective
study, a median trough CsA level of 218
ng/ml (range 96368) was effective in the
treatment of PRCA in cats.59
CsA is commonly used in veterinary dermatology. In a small retrospective study, CsA and
glucocorticoids were shown to be effective but
not superior to chlorambucil and glucocorticoids for the treatment of feline pemphigus
foliaceus; however, the studys low statistical
power may have contributed to the result of
non-superiority.68 CsA reduced the severity of
clinical signs in cats with atopic dermatitis
and performed similarly to prednisolone in a
randomized double-blinded clinical trial, but
this population was small as well.69 In a large
population of cats (n = 100) with atopic dermatitis, CsA at a dose of 7 mg/kg PO q24h
appeared to be effective and well tolerated,
with more cats improving with regard to their
lesions and pruritus compared with CsA at 2.5
mg/kg PO q24h or placebo.70 Cats induced
with CsA at a dosage of 7 mg/kg PO q24h had
their dose tapered to q48h after 4 weeks of
therapy and then again to twice weekly after
another 4 weeks, with over 50% of patients
remaining clinically stable.71
CsA continues to emerge as a promising
adjunctive/second-line immunomodulatory
agent for a variety of conditions. Most reported uses in our feline patients (with the excep-

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tion of allergic dermatitis in cats) are limited

to case reports or case series with small
populations. Larger prospective, placebocontrolled clinical trials are needed in order
to determine the extent of this drugs efficacy
as well as for comparison with other immunomodulatory agents. Consequently, glucocorticoids should still be considered the
cornerstone of therapy for the treatment of
immune-mediated disease in cats. CsA can be
considered as adjunctive therapy along with
glucocorticoids. It can be considered as sole
therapy in patients that cannot tolerate glucocorticoids, such as cats that develop diabetes
mellitus secondarily to glucocorticoidinduced insulin resistance.

Pimobendan
Although commonly used in feline medicine,
pimobendan (Vetmedin; Boehringer Ingelheim) has yet to be approved for use in cats.
It is a calcium sensitizer with both positive
inotropic and lusitropic effects. Pimobendan
works by inhibiting phosphodiesterase III
(PDE III), resulting in decreased breakdown
of cyclic adenosine monophosphate. This
process increases myocardial contractility
through increased release and reuptake of
calcium. PDE III inhibition also causes arterial
and venous dilation.
The most appropriate dosing regimen for
pimobendan in cats has yet to be established.
Pimobendan has been used clinically in cats
with evidence of ventricular systolic dysfunction,72 diastolic dysfunction73 and other
cardiac diseases74 at a dose of approximately
0.25 mg/kg PO q12h and appears to be well
tolerated. However, plasma concentrations
at this dose are 10-fold higher than those
observed in dogs, and the elimination half-life
of 1.3 h is almost three times as long.75 Side
effects appear to be uncommon. One cat with
systolic anterior motion of the anterior mitral
valve leaflet developed severe hypotension in
association with pimobendan administration.72 Other reported adverse effects include
anorexia and constipation74 as well as ptyalism and vomiting.75
Median survival time (MST) for cats with
congestive heart failure (CHF) secondary to
all types of cardiomyopathy treated with
pimobendan is reported to be between 151
and 167 days.72,74 These reports have no comparator group; therefore, it is difficult to draw
conclusions from these studies on whether or
not treatment with pimobendan significantly
improves survival. However, improved survival has been shown in cats with non-taurine
responsive dilated cardiomyopathy treated
with pimobendan (MST 49 days) compared
with controls (12 days) in a retrospective

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Clinically, pimobendan has been used successfully

in feline patients with many different types of
cardiomyopathy, including those in acute
congestive heart failure. Further studies are needed
to determine the limitations and all potential
contraindications of this medication.

study.76 Additionally, in a retrospective

review, cats with hypertrophic cardiomyopathy (and a few with hypertrophic obstructive
cardiomyopathy) treated with pimobendan
after the onset of CHF had a significantly
longer survival time (626 days) vs those not
treated with pimobendan (103 days).73
Despite the retrospective nature of the latter
studies, pimobendan appears to be a favorable treatment for acute and chronic CHF in
cats.
Pimobendan should be beneficial in cats
with many different types of cardiomyopathy
but theoretically should be avoided in cats
with hypertrophic obstructive cardiomyopathy as it may potentially worsen the
obstruction. Although one study reports a
possible benefit of pimobendan for CHF
secondary to hypertrophic obstructive cardiomyopathy,73 there are too few cats in this population to make any generalizations at this
time. Pimobendan in cats remains an extralabel therapeutic, and consultation with a veterinary cardiologist is always recommended.

Clopidogrel
Clopidogrel bisulfate (Plavix; Bristol-Myers
Squibb) is a thienopyridine class platelet
inhibitor that works by irreversibly inhibiting
the adenosine diphosphate receptor P2Y12 on
the platelet membrane. It is a prodrug that is
metabolized via cytochrome P450-dependent
pathways into active metabolites. Clopidogrel
inhibits platelet aggregation as well as causing platelet aggregates to disaggregate more
easily.77 In healthy cats, platelet aggregation
was inhibited by clopidogrel by day 3 when
administered at high doses (75 mg/kg PO
q24h) and moderate doses (37.5 mg PO
q24h).78 Cats given a low dose of 18.75 mg PO
q24h demonstrated inhibition of platelet
aggregation at day 7 (earlier time points were
not evaluated in these low-dose cats). Platelet
aggregation for all doses was similar to
baseline by day 7 after discontinuation of
the medication. No adverse effects were
appreciated. Based on these results, the
dosage of clopidogrel recommended for cats

is 18.75 mg/cat PO q24h. Clopidogrel should

be discontinued for 7 days prior to any procedure where hemorrhage is an anticipated
complication.
The main use of clopidogrel in cats has been
for the prevention of arterial thromboembolism (ATE), a devastating condition that
affects our feline patients. The most common
cause of thromboembolic disease in cats is
cardiomyopathy, but conditions in which
there is loss of antithrombin such as proteinlosing nephropathy and protein-losing
enteropathy may also result in hypercoagulability and thromboembolic disease. ATE is
associated with a high morbidity and mortality rate and often occurs without prior warning. In a recent retrospective study evaluating
250 cats with ATE that were brought to primary care facilities, 61.2% were euthanized on
presentation.79 Of the remaining cats in which
treatment was attempted, 30% died or were
euthanized within 24 h and 40% within
7 days. MST for the remaining 30% was 94
days. Overall, 98% of the 250 cats died or were
euthanized within 12 months of initial presentation. No factors were identified that predicted survival for 7 days. Although receiving
heparin and not receiving aspirin or clopidogrel were reported as independent predictors
of mortality within the first week after presentation, these results must be interpreted with
caution as there may have been bias towards
giving oral medications to those patients
thought to have clinically less severe disease.
Clopidogrel unfortunately was not shown
to increase the thrombolytic rate of tissueplasminogen activator in an in vitro study
using feline whole blood.80 As a result, it is not
expected to significantly enhance the breakdown of preformed blood clots but, rather,
is used to try to prevent new thrombus
formation.
Veterinary clinical trials have failed to
reveal a clear-cut superior antithrombotic
agent for the prevention of ATE. Because of
the increased number of platelets associated
with arterial clots vs venous clots, platelet
inhibitors such as clopidogrel or aspirin
theoretically are a good treatment option.
Recently, a prospective, double-blinded, multicenter study evaluated the use of clopidogrel
(18.75 mg PO q24h) and aspirin (81 mg PO
q72h) for the prevention of recurrent cardiogenic ATE and mortality in cats.81 Treatment
with clopidogrel resulted in significantly
improved outcomes, with an MST to a recurrent ATE event of 443 days for the clopidogrel
group vs 192 days for the aspirin group.
Both aspirin and clopidogrel are reported to
be well tolerated in cats. With the recent availability of generic clopidogrel, it has become
an even more appealing therapeutic now that

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the difference in cost is minimal. Additionally,

while there is no clear advantage to using
both medications concurrently, this treatment
regimen can be considered because of their
slightly different mechanisms of action.
There is no reliable and readily available
method for monitoring feline patients receiving
clopidogrel. However, a recent study evaluating the use of Plateletworks, a screening assay
used in human medicine to assess platelet
aggregation, has shown that it holds some
promise as a diagnostic tool to monitor clopidogrel therapy in cats.82 Clopidogrel appears to be
well tolerated in cats.78 Nevertheless, bleeding
remains a potential complication with the use

Table 2

of any anticoagulant. The development of nonregenerative anemia in cats on long-term

clopidogrel therapy has also anecdotally been
reported.77

The main use of clopidogrel in cats is

for the prevention of arterial thromboembolism
(ATE). However, cats with recurrent cardiogenic
ATE given clopidogrel versus aspirin have
improved outcomes.

Ten novel pharmaceuticals: summary of the clinical indications and reported adverse effects in cats

Drug

Clinical indications

Robenacoxib

Approved indications
< Acute (short-term) postoperative pain and inflammationUSA,EU
< Acute pain and inflammation associated with musculoskeletal
disordersUSA,EU

Adverse effects

Pradofloxacin

Approved indications
< Infected wounds and abscessesUSA,EU
< Bacterial upper respiratory infectionsEU

< GI toxicity including ulceration

< Nephrotoxicity
< Potential for retinotoxicity

Reported indications
< Bacterial urinary tract infections
< Hemotropic mycoplasmosis
< Lethargy, anorexia and vomiting
< Potential for similar effects seen with other
cephalosporins (ie, hypersensitivity reactions)

Cefovecin

Approved indications
< Skin and soft tissue infectionsUSA,EU
< Bacterial lower urinary tract infectionsEU

Minocycline

Reported indications
< Similar spectrum of activity as doxycycline
< Methicillin-resistant Staphylococcus pseudintermedius

< GI toxicity
< Potential for esophageal strictures
< Potential for urticaria and hypotension with
rapid IV bolus
< Potential to retard fetal skeletal development and
discolor deciduous teeth
<
<
<
<
<
<

Ciclosporin
Approved indications
(cyclosporine) < Allergic dermatitisUSA,EU
Reported indications
< Pemphigus foliaceus
< Pure red cell aplasia
< Primary immune-mediated thrombocytopenia
< Eosinophilic keratitis
< Immune-mediated polyarthritis
Pimobendan

Reported indications
< Ventricular systolic dysfunction
< Congestive heart failure secondary to cardiomyopathy

Clopidogrel

Reported indications
< Prevention of arterial thromboembolism

Mirtazapine

Reported indications
< Anorexia associated with CKD or other disorders

Famciclovir

Reported indications
< Feline herpesvirus-1

Oclacitinib

Reported indications
< Potential treatment for feline asthma
< Potential treatment for feline allergic dermatitis

Approved uses in the United States and in Europe are denoted by

kidney disease

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GI toxicity
Gingival hyperplasia
Opportunistic infections (ie, toxoplasmosis)
Possible hemolytic uremic syndrome
Anaphylaxis after IV administration
Possible development of malignant neoplasia
(ie, lymphoma)

< GI toxicity
< Hypotension
< Hemorrhage
< Non-regenerative anemia

< Vocalization
< Behavior changes (increased interaction/sociability)

< None reported in a small population of cats for 28 days

USA

and

EU

, respectively; IV = intravenous; GI = gastrointestinal; CKD = chronic

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Table 3

Ten novel pharmaceuticals: reported doses in cats based on pharmacokinetic/pharmacodynamic

studies and clinical use

Drug

Dosage

References

Robenacoxib

Tablet
12 mg/kg PO q24h x 3 days on an empty stomachUSA
1 mg/kg PO q24h x 6 days on an empty stomachEU

Label information; Onsior: Novartis Animal Health

European Medicines Agency: European Public
Assessment Report for Onsior

Injectable solution
2 mg/kg SC q24h x 2 daysEU
Pradofloxacin

Tablet
34.5 mg/kg PO q24hEU

Freedom of Information Summary: NADA 141344

National Office of Animal Health Compendium of Animal
Medicines: Veraflox tablets and 25 mg/ml oral suspension
for cats

Oral suspension
7.5 mg/kg PO q24hUSA
57.5 mg/kg PO q24hEU
Cefovecin

8 mg/kg SC once
If required, an additional dose may be administered 14 days after the
first injection (labeled in Europe only for skin and soft tissue infections)

Label information; Convenia: Pfizer Animal Health

Minocycline

8.8 mg/kg PO q24h

50 mg/cat PO q24h

Compartmental pharmacokinetics model in laboratory

cats [abstract]41

Ciclosporin
2.55 mg/kg PO, IV q12h
(cyclosporine) 7 mg/kg PO q24h

Retrospective case-control study59

Randomized, blinded, placebo-controlled clinical trial66
Randomized, double-blinded, placebo-controlled clinical
trial70

Pimobendan

0.25 mg/kg PO q12h

Retrospective cohort studies72,74

Retrospective case-control study73

Clopidogrel

18.75 mg/cat PO q24h

Prospective, cross-over observational study78

Mirtazapine

1.88 mg/cat PO q24h in healthy cats

1.88 mg/cat PO q48h in cats with CKD

Non-compartmental pharmacokinetics model in healthy

cats83
Non-compartmental pharmacokinetics model in cats
with CKD84

Famciclovir

62.5 mg/cat PO q24h x 7 days, then q48h x 10 days

62.5 mg/cat PO q12h x 2130 days
62.5 mg/cat PO q24h x 7 days, then q12h x 743 days
62.5 mg/cat PO q24h x 120 days
125 mg/cat PO q8h x 1442 days

Case reports and expert opinion93

Oclacitinib

0.5 mg/kg PO q12h

Unpublished data

USA

and EU denote labeled dose in the United States and in Europe, respectively; PO = orally; SC = subcutaneously; IV = intravenously;
CKD = chronic kidney disease

Mirtazapine
Anorexia is a common presenting complaint in
our feline patients, and a comprehensive diagnostic evaluation is recommended to identify
the underlying cause in each case. In some
instances a progressive, irreversible disease such
as chronic kidney disease (CKD) is identified.
The clinical approach to management of anorexia in cats is to treat the identified underlying
disease and provide supportive care, which
may include placement of a feeding tube
and/or administration of an appetite stimulant.
Mirtazapine is a tetracyclic antidepressant causing antagonism at central pre-synaptic 2 receptors, 5HT2, 5HT3, and H1 receptors. Antagonism of 5HT3 receptors likely accounts for the
majority of mirtazapines antiemetic and antinausea effects, while antagonism of 2 receptors
contributes to appetite stimulation through an
increase in norepinephrine concentration.

Until recently, recommended dosing for cats

was extrapolated from humans or based on
anecdotal reports. In young healthy cats,
doses of 1.88 mg/cat and 3.75 mg/cat were
shown to produce similar increases in
appetite compared with placebo; however,
there was a significant increase in side effects
(vocalization and interaction/sociability) with
the higher dose compared with the lower
dose.83 The half-life of mirtazapine in the
population dosed at 1.88 mg/cat was 9.2 h.
In cats with CKD, the half-life was 15 h, with
a significant negative correlation found
between serum creatinine and clearance of
mirtazapine.84 Drug accumulation is possible
with daily dosing in cats with renal disease,
but not with q48h dosing. In a placebocontrolled, double-blinded, crossover clinical
trial, mirtazapine administered at 1.88 mg
PO q48h for 3 weeks significantly increased
activity, appetite and weight, and decreased

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Mirtazapine is an effective appetite stimulant as

well as antiemetic. Diagnostics looking for the
underlying cause of anorexia are recommended
prior to initiating this therapy in every case.
vomiting compared with placebo in cats with
CKD.85 There is also some evidence that
metabolism of mirtazapine is decreased in
older cats without renal insufficiency,84 but the
need for dose reduction in this population has
not been shown yet.
Mirtazapine undergoes hepatic metabolism
and renal excretion. Dosing mirtazapine q48h
seems to be tolerated well in cats with CKD.84
There are currently no reports evaluating
differences in pharmacokinetics in cats with
hepatic dysfunction. In human patients with
hepatic dysfunction the half-life of mirtazapine increased by 39%, suggesting dose
adjustment is needed in patients with
impaired hepatic function.86 Similarly, it is reasonable to consider dose reduction in feline
patients with advanced hepatic dysfunction
or markers of hepatic failure.
No reports to date evaluate the efficacy and
safety of long-term use of mirtazapine in cats
with CKD. However, it is of anecdotal benefit
to many cats with CKD, without the development of adverse effects requiring discontinuation of the medication. Risk of development of
serotonin syndrome is considered to be low,
and cyproheptadine has been considered as
an antidote.87 Consequently, it is not recommended that mirtazapine and cyproheptadine
are given concurrently for appetite stimulation, considering their actions may cancel
each other out.88

Famciclovir
FHV-1 is a common cause of upper respiratory tract disease and ophthalmic disease in
cats. Famciclovir (Famvir; Novartis Animal
Health) is an antiviral that, although not currently licensed for use in cats, is commonly
used to treat this infection. In cats, oral
famciclovir is absorbed and converted to
penciclovir, reaching maximum plasma
concentrations in approximately 3 h.89,90
Penciclovir is then converted into penciclovir
triphosphate by virus-induced thymidine
kinase present in cells infected by -herpesviruses. It is penciclovir triphosphate that
inhibits viral DNA polymerase, thus inhibiting viral DNA synthesis and viral replication.
As such, famciclovir is considered virostatic
along with all other antivirals currently used
for the treatment of FHV-1 infections.

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Based on in vitro data, the target plasma

concentration or half maximal inhibitory
concentration (IC50) of penciclovir against
FHV-1 is 3.5 g/ml.91 Penciclovir maximum
observed plasma concentration (Cmax) and
time to Cmax for doses of 40 mg/kg PO and 90
mg/kg PO are similar at around 1.3 g/ml
and 2.8 h.90 These results suggest that famciclovir metabolism may become saturated at
these doses and that efficacy of the lower
dose may be similar to that of the higher dose.
A prior study evaluated penciclovir pharmacokinetics in cats at a lower dose (15 mg/kg
PO) but found the Cmax to be 0.35 g/ml,
a value even further from the target
concentration.89
In a prospective, placebo-controlled clinical
trial in cats experimentally infected with FHV1, cats treated with famciclovir (90 mg/kg PO
q8h for 21 days) had lower disease scores,
lower conjunctivitis histologic scores, shed
less herpetic DNA, and at the end of the study
had lower levels of circulating anti-FHV-1
antibodies compared with controls.92
Famciclovir-treated cats also gained weight
throughout the study, whereas control cats
lost weight. In a case series famciclovir was
reported to be effective and well tolerated in
the treatment of clinical signs associated with
FHV-1 infections involving the eyes (ie, conjunctivitis, keratitis, corneal sequestra), upper
respiratory tract (ie, rhinosinusitis) and skin
(ie, dermatitis).93 All nine adult cats treated
with oral famciclovir experienced clinical
improvement that was considered superior to
their previous reported response to other
supportive therapies. The treatment regimens
used for famciclovir varied between cats and
included 62.5 mg/cat PO q24h for 7 days, then
q48h for 10 days; 62.5 mg/cat PO q12h for
2130 days; 62.5 mg/cat PO q24h for 7 days,
then q12h for 743 days; 62.5 mg/cat PO q24h
for 120 days; and 125 mg/cat PO q8h for
1442 days.93
Reported adverse effects of famciclovir are
limited to those from small studies or
described in anecdotal observations. Famciclovir has been used successfully in kittens
and queens for the treatment of FHV-1 in the
shelter setting.93 However, safety studies evaluating the administration of famciclovir to
pregnant queens have not been conducted.
Famciclovir appears to be well tolerated in
adult cats. Reported side effects include a
decrease in packed cell volume and total

Famciclovir is an antiviral that, although not

currently licensed for use in cats, is commonly
used to treat feline herpesvirus-1.

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protein as well as an increase in white blood

cell count due to an increase in neutrophils
and monocytes.89 These changes may, however, be due to multiple blood draws and
stress. Another study showed no changes in
lab work (complete blood count, biochemical
panel, urinalysis) suggestive of drug
toxicosis.92
Famciclovir appears to be a viable option
for both kittens and adult cats in the treatment
of many of the manifestations of FHV-1 infections including keratitis, conjunctivitis, rhinosinusitis and dermatitis. Its use in kittens is
advised to be limited to those with severe or
persistent disease.94 A dosage recommendation of 4090 mg/kg PO q8h is reported to be
well tolerated;95 however, the most appropriate treatment regimen for famciclovir has yet
to be determined.

Oclacitinib
Oclacitinib (Apoquel; Pfizer) is approved in
the United States and Europe for the treatment of pruritis and inflammation associated
with atopic dermatitis in dogs. It is a novel
Janus kinase (JAK) inhibitor that has activity
against JAK1-dependent cytokines. JAK
enzymes are important in cytokine signaling,
particularly those involved in pro-inflammatory, pro-allergic and pruritogenic conditions.
As such, it has shown promise as a safe and
effective treatment for atopic dermatitis in
dogs.96
Although no published studies are available
reporting the pharmacokinetics or clinical use
of JAK inhibitors in cats, an abstract described
the use of a JAK inhibitor as a novel treatment
for feline asthma. In an experimental model
of asthma in 24 cats, a novel JAK inhibitor
administered at a dose of 0.5 mg/kg or
1 mg/kg PO q12h for 28 days significantly
reduced eosinophilic airway inflammation
compared with placebo (unpublished data
presented at the American College of
Veterinary Internal Medicine Forum 2013,
Seattle, WA). There was no significant difference in the reduction of inflammation
between the two doses, and there was no significant difference between the study drug
and placebo with regards to ventilatoracquired pulmonary mechanics with methacholine challenge. No adverse effects or
clinically relevant laboratory abnormalities
were observed.
In a group of 21 cats with IL-31 induced
pruritis, oclacitinib administered at 0.4 mg/kg
and 1 mg/kg PO 1 h prior to IL-31 injection
significantly reduced pruritis by 63% and
62%, respectively. However, oclacitinib
administered at a dose of 0.4 mg/kg PO 12 h
prior to IL-31 injection failed to reduce pruritis

Prospective studies in cats with naturally occurring

asthma and allergic dermatitis are needed before
oclacitinib can be recommended for clinical use.

(unpublished data presented at the American

Academy of Veterinary Pharmacology and
Therapeutics Biennial Symposium 2013,
Potomac, MD).
JAK inhibitors may prove to be a beneficial
adjunctive therapy with glucocorticoids or a
potential alternative to glucocorticoids for the
treatment of feline asthma. There may also be
a potential role for oclacitinib in the treatment
of feline allergic dermatitis. Prospective studies in cats with naturally occurring disease are
needed before this medication can be recommended for clinical use.

Summary
Clinical indications, adverse effects and dosing recommendations for the 10 medications
discussed in this review are summarized in
Tables 2 and 3.

Funding
The authors received no specific grant from any
funding agency in the public, commercial or notfor-profit sectors for the preparation of this article.

Conflict of interest
The authors have no conflict of interest to declare.

KEY POINTS
< Veterinary medicine continues to be
a dynamic field requiring clinicians to
constantly modify their clinical practice.

< The pharmaceuticals discussed in this

review article are only a select few out

of many with new information pertaining
to their clinical use.

< It is likely that knowledge of even these

medications will continue to expand over

the next several years.

< Feline practitioners are strongly

encouraged to familiarize themselves

with any novel therapeutic and to
seek evidence-based guidance
whenever possible.

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